The adaptive immune system is comprised of antibodies, generated by B-cells, and cell mediated immunity which depends on the recognition by T-cells of peptides bound in the major histocompatibility molecules and presented on the surface of antigen presenting cells (APCs). Many cell types may serve as APCs, but primarily they comprise dendritic cells, macrophages, and B-cells (the so called “professional” APCs). While each B-cell becomes dedicated to the production of one antibody sequence, that sequence is derived as the product of somatic hypermutation (SHM) of the genes in that B-cell that encode the immunoglobulin variable region. The presentation of peptides bound in MHC molecules is a function of cleavage of polypeptides by various endosomal peptidases, including but not limited to cathepsins, and the competitive binding of peptides to genetically defined MHC molecules. Hence, the presentation to antigens by the immune system is the combination of stochastic, innate, and genetically determined events.
The primary function of the adaptive immune system is to differentiate self from not-self and to allow the body to mount an appropriate response to molecules, once identified as self or as not-self. When a familiar self-antigen is recognized, the desired outcome is down-regulation of the immune response or tolerance. When an unfamiliar non-self-antigen is encountered, the appropriate outcome is usually a robust up-regulation to yield an immune response in which cytokine responses enlist additional cellular responses to remove the foreign stimulus and protect the integrity of the host.
The discrimination between self and not-self is largely dependent on the T-cell responses and is the combination of the host's genetically determined MHC molecules in combination with motifs comprised in peptides which are bound by MHC molecules and exposed to T-cells in the context of the MHC molecules.
There is a need to be able to predict peptide sequences which comprise motifs that are likely to be recognized by T-cells, and to identify those motifs which are likely to give rise to down-regulation or suppression of the immune response (sometimes termed “Tregitopes” [1]) and those which are likely to result in up-regulation or activation of the immune response (T-helper activity). Having the ability to identify T cell epitopes most likely to upregulate or downregulate an immune response then enables the design of a number of interventions including the design of vaccines with improved properties and the ability to specifically target T cell populations and to reduce or eliminate such populations.